L. Guohttp://repub.eur.nl/ppl/6818/
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RePub, Erasmus University RepositoryCiprofloxacin in polyethylene glycol-coated liposomes: Efficacy in rat models of acute or chronic Pseudomonas aeruginosa infectionhttp://repub.eur.nl/pub/55143/
Tue, 01 Jan 2002 00:00:01 GMT<div>I.A.J.M. Bakker-Woudenberg</div><div>M.T. ten Kate</div><div>L. Guo</div><div>P. Working</div><div>J.W. Mouton</div>
Ciprofloxacin in polyethylene glycol-coated liposomes: efficacy in rat models of acute or chronic Pseudomonas aeruginosa infectionhttp://repub.eur.nl/pub/9935/
Tue, 01 Jan 2002 00:00:01 GMT<div>I.A.J.M. Bakker-Woudenberg</div><div>M.T. ten Kate</div><div>L. Guo</div><div>P. Working</div><div>J.W. Mouton</div>
In a previous study in experimental Klebsiella pneumoniae pneumonia, the
therapeutic potential of ciprofloxacin was significantly improved by
encapsulation in polyethylene glycol-coated ("pegylated") long-circulating
(STEALTH) liposomes. Pegylated liposomal ciprofloxacin in high doses was
nontoxic and resulted in relatively high and sustained ciprofloxacin
concentrations in blood and tissues, and hence an increase in the area
under the plasma concentration-time curve (AUC). These data correspond to
data from animal and clinical studies showing that for fluoroquinolones
the AUC/MIC ratio is associated with favorable outcome in serious
infections. Clinical failures and the development of resistance are
observed for marginally susceptible organisms like Pseudomonas aeruginosa
and for which sufficient AUC/MIC ratios cannot be achieved. In the present
study the therapeutic efficacy of pegylated liposomal ciprofloxacin was
investigated in two rat models of Pseudomonas aeruginosa pneumonia. In the
acute model pneumonia developed progressively, resulting in a rapid onset
of septicemia and a high mortality rate. Ciprofloxacin twice daily for 7
days was not effective at doses at or below the maximum tolerated dose
(MTD). However, pegylated liposomal ciprofloxacin either at high dosage or
given at low dosage in combination with free ciprofloxacin on the first
day of treatment was fully effective (100% survival). Obviously, prolonged
concentrations of ciprofloxacin in blood prevented death of the animals
due to early-stage septicemia in this acute infection. However, bacterial
eradication from the left lung was not effected. In the chronic model,
pneumonia was characterized by bacterial persistence in the lung without
bacteremia, and no signs of morbidity or mortality were observed.
Ciprofloxacin administered for 7 days at the MTD twice daily resulted in
killing of more than 99% of bacteria in the lung; this result can also be
achieved with pegylated liposomal ciprofloxacin given once daily. Complete
bacterial eradication is never observed.Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats.http://repub.eur.nl/pub/12926/
Mon, 07 May 2001 00:00:01 GMT<div>I.A.J.M. Bakker-Woudenberg</div><div>M.T. ten Kate</div><div>L. Guo</div><div>P. Working</div><div>J.W. Mouton</div>
Animal and clinical data show that high ratios of the area under the
concentration-time curve and the peak concentration in blood to the MIC of
fluoroquinolones for a given pathogen are associated with a favorable
outcome. The present study investigated whether improvement of the
therapeutic potential of ciprofloxacin could be achieved by encapsulation
in polyethylene glycol (PEG)-coated long-circulating sustained-release
liposomes. In a rat model of unilateral Klebsiella pneumoniae pneumonia
(MIC = 0.1 microg/ml), antibiotic was administered at 12- or 24-h
intervals at twofold-increasing doses. A treatment period of 3 days was
started 24 h after inoculation of the left lung, when the bacterial count
had increased 1,000-fold and some rats had positive blood cultures. The
infection was fatal within 5 days in untreated rats. Administration of
ciprofloxacin in the liposomal form resulted in delayed ciprofloxacin
clearance and increased and prolonged ciprofloxacin concentrations in
blood and tissues. The ED(50) (dosage that results in 50% survival) of
liposomal ciprofloxacin was 3.3 mg/kg of body weight/day given once daily,
and that of free ciprofloxacin was 18.9 mg/kg/day once daily or 5.1
mg/kg/day twice daily. The ED(90) of liposomal ciprofloxacin was 15.0
mg/kg/day once daily compared with 36.0 mg/kg/day twice daily for free
ciprofloxacin; 90% survival could not be achieved with free ciprofloxacin
given once daily. In summary, the therapeutic efficacy of liposomal
ciprofloxacin was superior to that of ciprofloxacin in the free form.
PEG-coated liposomal ciprofloxacin was well tolerated in relatively high
doses, permitting once daily administration with relatively low
ciprofloxacin clearance and without compromising therapeutic efficacy.